Regulation of Masking and Circadian Rhythm Phase

描述(申请人提供)：负掩蔽是当哺乳动物暴露在光下时对夜间运动活动的抑制。一方面，它被认为是昼夜节律评估的不便之处，因为它可能掩盖潜在的事件。另一方面，掩蔽本身也被研究过，而且已知是由相同类别的光感受器介导的，这些光感受器介导光诱导的相移。事实上，尽管光诱导的掩蔽被认为与光诱导的相移有根本的不同，但真正能说明这一问题的唯一数据来自两项视交叉上核(SCN)损伤研究。其中更仔细的支持这样一种观点，即SCN对于每一种反应都是必要的，通过外推，它是两者的起源。这一观点也与大量数据一致，这些数据表明，光和运动活动可以相互抑制对方对昼夜节律的影响。这项建议使用老鼠来解决昼夜节律视觉系统的两个基本问题。行为分析将允许比较毫秒光刺激(数量、强度、闪光间隔)对掩蔽和相移的影响。用类比的方法论证，这两种反应同样受光的调制，因此很可能受相同的输入通路和视网膜核(SCN)控制。转基因小鼠(黑素蛋白缺乏(Opn4-/-)和视杆/视锥退化(Rd-/Rd-))将被用来消除不同的光感受器的功能，并确定相同的光感受器在多大程度上调节掩蔽和相移。他们还将确定ipRGCs是否是调节相移和掩蔽的SCN光接收途径的必要部分，即使此类细胞不含黑素光色素。结论研究将使用化学、刀切、损伤和轨迹追踪方法来明确确定SCN是否同时参与相移和掩蔽，以及相同的大脑区域或通路是否参与了光诱导睡眠现象。这一点特别重要，因为到目前为止，还没有解剖学或生理学证据表明，光对掩蔽、相移或光诱导睡眠的影响可以在SCN细胞水平上区分开来。这些结果有望极大地提高我们对光输入通路的解剖学、生理学和功能的理解，光输入通路介导昼夜节律相移、掩蔽和光诱导睡眠。使用非常短(毫秒)的光刺激将为研究调节这三种行为的过程提供一种新的方法。与公共健康相关的生理和行为昼夜节律通过一条涉及几种不同光感受器类型的通路与光信号同步。该项目利用新的光刺激、新的测试程序和小鼠模型来辨别哪些光感受器、神经通路和大脑区域对节律计时以及光抑制运动和诱导睡眠的能力起作用。研究还旨在促进对视觉健康和正常功能的基本了解。为了开发临床护理方法，为患有延迟相睡眠综合症、季节性情感障碍、睡眠时机不当或其他身体节律的人，有必要了解光刺激是如何作用和调节昼夜节律系统的，以及它如何与睡眠和唤醒有关。

DESCRIPTION (provided by applicant): Negative masking is the suppression of nocturnal locomotor activity that occurs when a mammal is exposed to light. On the one hand, it has been considered to be either an inconvenience for circadian rhythm assessment insofar as it can obscure underlying events. On the other, masking has been studied for its own sake and is known to be mediated by the same classes of photoreceptors that mediate light-induced phase shifts. In fact, although light-induced masking has been considered to be fundamentally different from light-induced phase shifts, the only data that actually speak to the issue come from two suprachiasmatic nucleus (SCN) lesion studies. The more careful of these supports the view that the SCN is necessary for each response and, by extrapolation, is the origin of both. This view is also consistent with substantial data showing that light and locomotor activity can mutually inhibit each other's effect on circadian phase. This proposal uses mice to address two issues fundamental to the circadian visual system. Behavioral analysis will allow comparison of the effects of millisecond light stimuli (number, intensity, inter-flash interval)on masking and phase shifts. An argument by analogy will be made in support of the proposition that these two responses are similarly modulated by light and, therefore, likely to be controlled by the same input pathway and retinorecipient nucleus (SCN). Transgenic mice (melanopsin deficient (Opn4-/-) and rod/cone degenerate (rd-/rd-)) will be used to eliminate function the various photoreceptors and determine the extent to which masking and phase shifts are mediated by the identical photoreceptors. They will also determine whether ipRGCs are a necessary part of the photoreception pathway to the SCN that mediates both phase shifts and masking, even if such cells do not contain melanopsin photopigment. Concluding studies will use a chemical, and knife cut, lesion and tract tracing methods to explicitly determine whether or not the SCN mediates both phase shifts and masking, and whether the same brain regions or pathways are involved in the phenomenon of light-induced sleep. This is particularly important because there is, as yet, no anatomical or physiological evidence that effects of light on masking, phase shifts or light-induced sleep can be distinguished at the level of SCN cells. The results are expected to greatly improve our understanding of the anatomy, physiology and function of the photic input pathway mediating circadian rhythm phase shifts, masking and light- induced sleep. The use of very brief (millisecond) photic stimuli will provide a novel approach for studying processes regulating those three behaviors. PUBLIC HEALTH RELEVANCE Physiological and behavioral circadian rhythms are synchronized to light signals by a pathway involving several different photoreceptor types. This project utilizes novel light stimuli, new test procedures and mouse models to discern which photoreceptors, neural pathways and brain regions contribute to rhythm timing and to the ability of light to suppress locomotion and induce sleep. Studies are also designed to promote basic understanding of visual health and normal function. In order to develop methods of clinical care for persons suffering from such problems as delayed phase sleep syndrome, seasonal affective disorder, inappropriate timing of sleep or other bodily rhythms, it is necessary to understand how photic stimuli act upon, and regulate, the circadian rhythm system, and how it relates to sleep and arousal.